Antihypertensive 3-piperidinyl-indazole derivatives

ABSTRACT

3-Piperidinyl-indazole derivatives and their pharmaceutically acceptable acid addition salts being useful antagonists of neurotransmitters; pharmaceutical compositions containing the same and a method of treating warm-blooded animals suffering from diseases associated with the release of said neutrotransmitters.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of our copending application Ser. No.239,915, filed Sep. 2, 1988, now abandoned.

BACKGROUND OF THE INVENTION

A number of 3-piperidinyl-1,2-benzisoxazoles and3-piperidinyl-1,2-benzisothiazoles having antiserotonin andantipsychotic activity are known from U.S. patent application No.4,804,663 and J. Med. Chem. 1985, 28, 761-769. In EP-A-0,135,781,published Apr. 3, 1985, there are disclosed a number of3-piperidinyl-indazole derivatives as antipsychotics and analgesics.

DESCRIPTION OF THE INVENTION

The present invention is concerned with novel 3-piperidinyl-indazolederivatives having the formula ##STR1## the pharmaceutically acceptableacid addition salts and stereochemically isomeric forms thereof, wherein

R¹ is hydrogen or C₁₋₆ alkyl;

R² is hydrogen; C₁₋₆ alkyl; hydroxyC₁₋₆ alkyl; phenyl optionallysubstituted with up to three substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy, halo, amino, nitro andtrifluoromethyl; arylC₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆alkyloxycarbonyl or phenylcarbonyl, wherein phenyl is optionallysubstituted with up to three substituents independently selected fromC₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy, halo, amino, nitro andtrifluoromethyl;

R³ and R⁴ each independently are hydrogen, halo, hydroxy, C₁₋₆ alkyloxyor C₁₋₆ alkyl;

Alk is C₁₋₄ alkanediyl; and

Q is a bicyclic heterocyclic radical of formula ##STR2## wherein R⁵ ishydrogen or C₁₋₆ alkyl;

Z is --S-- or --CR⁶ ═CR⁷ --; said R⁶ and R⁷ each independently beinghydrogen or C₁₋₆ alkyl; or Z is --CH₂ -- wherein one hydrogen atom maybe replaced by hydroxy or C₁₋₆ alkyl;

A is a bivalent radical --CH₂ --CH₂ -- or --CH₂ --CH₂ --CH₂ -- whereinin the latter two radicals one or two hydrogen atoms may be replaced byC₁₋₆ alkyl; or A is a bivalent radical --CR⁸ ═CR⁹ --, wherein R⁸ and R⁹each independently are hydrogen, halo, amino or C₁₋₆ alkyl; or when Z is--S--, then A may also be --CR¹⁰ ═N--, R¹⁰ being hydrogen or C₁₋₆ alkyl;or when Z is --CR⁶ ═CR⁷ --, then A also may be --O--; and

Y¹ and Y² each independently are O or S;

R¹¹ is hydrogen, halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy, trifluoromethyl,nitro, amino, mono- or di(C₁₋₆ alkyl)amino, C₁₋₁₀ alkylcarbonylamino,cyano, hydroxy, C₁₋₁₀ alkylcarbonyloxy, phenylmethoxy or azido;

R¹² is hydrogen or halo; and aryl is phenyl optionally substituted withup to three substituents independently selected from C₁₋₆ alkyl, C₁₋₆alkyloxy, hydroxy, halo, amino, nitro and trifluoromethyl; pyridinyl,furanyl or C₁₋₆ alkyl substituted furanyl.

In formula (I) the dotted lines within the indazole moiety represent aconjugated diene system, its precise location depending upon theposition of the R² radical: when said R² is substituted on N¹, then thedouble bonds are located between N² and position 3 and between positions3a and 7a of the indazole system; if on the other hand, R² issubstituted on N², then the double bonds are located between positions 3and 3a and between positions 7a and N¹ of the indazole system.

In the foregoing definitions the term halo is generic to fluoro, chloro,bromo and iodo; C₁₋₆ alkyl defines straight and branch chained saturatedhydrocarbon radicals, having from 1 to 6 carbon atoms, such as, forexample, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl and the like; C₁₋₁₀alkyl defines C₁₋₆ alkyl radicals as defined hereinabove and the higherhomologs thereof having from 7 to 10 carbon atoms; C₁₋₄ alkanediyldefines bivalent straight or branch chained hydrocarbon radicals havingfrom 1 to 4 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomersthereof.

The moiety Z-A in the radical of formula (b) in particular may be--S--CH₂ --CH₂ --, --S--CH₂ --CH₂ --CH₂ --, --S--CH═C(CH₃)--,--S--C(CH₃)═N--, --CH═CH--CH═CH--, --C(CH₃)═CH--CH═CH--,--CH═CH--C(CH₃)═CH--, --CH═CH--CCl═CH--, --CH═CH--CBr═CH--,--CH═C(CH₃)--O--, --CH₂ --CH₂ --CH₂ --CH₂ --, --CHOH--CH₂ --CH₂ --CH₂--, --CH(CH₃)--CH₂ --CH₂ --CH₂ --, --CH₂ --CH(CH₃)--CH₂ --CH₂ -- or--CH(CH₃)--CH₂ --CH(CH₃)--CH₂ --.

Depending on the nature of the various substituents the compounds offormula (I) may have several asymmetric carbon atoms. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure. The absolute configuration of each chiral centermay be indicated by the stereochemical descriptors R and S, this R and Snotation corresponding to the rules described in Pure Appl. Chem. 1976,45, 11-30. Stereochemically isomeric forms of the compounds of formula(I) are obviously intended to be embraced within the scope of theinvention.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereoisomersmay be separated by physical separation methods such as selectivecrystallization and chromatographic techniques, e.g., counter currentdistribution, liquid chromatography and the like; and enantiomers may beseparated from each other by the selective crystallization of theirdiastereomeric salts with optically active acids. Pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically.

Preferred compounds within the present invention are those compounds offormula (I) wherein R¹ is hydrogen; and/or R² is substituted on N¹,and/or R³ and R⁴ each independently are hydrogen, C₁₋₆ alkyloxy or halo;and/or Q is a radical of formula (a) wherein R⁵ is C₁₋₆ alkyl.

Particularly preferred compounds are those preferred compounds whereinR² is hydrogen, C₁₋₆ alkyl, phenyl optionally substituted with halo ortrifluoromethyl, or phenylmethyl optionally substituted with halo, C₁₋₆alkyloxy or trifluoromethyl; and/or R³ is halo; and/or R⁴ is hydrogen.

The most preferred compounds are those particularly preferred compoundswherein R³ is 6-fluoro.

The compounds of formula (I) can generally be prepared by N-alkylatingan appropriately substituted piperidine of formula (III) with analkylating agent of formula (II). ##STR3## In formula (II) and in anyformula hereinafter wherein it occurs, W represents a reactive leavinggroup such as, for example, halo, e.g. chloro, bromo or iodo, or asulfonyloxy group, e.g. methanesulfonyloxy, benzenesulfonyloxy,4-methylbenzenesulfonyloxy and the like.

The reaction of (II) with (III) can conveniently be conducted in areaction-inert solvent such as, for example, an aromatic hydrocarbon,e.g., benzene, methylbenzene, dimethylbenzene, and the like; a loweralkanol, e.g., methanol, ethanol, 1-butanol and the like; a ketone,e.g., 2-propanone, 4-methyl-2-pentanone and the like; an ether,1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like;N,N-dimethylformamide; N,N-dimethylacetamide; nitrobenzene;1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone;1,3-dimethyl-2-imidazolidinone; 1-methyl-2-pyrrolidinone; and the like.The addition of an appropriate base such as, for example, an alkali oran earth alkaline metal carbonate, hydrogen carbonate, hydroxide,alkoxide or hydride, e.g., sodium carbonate, sodium hydrogen carbonate,potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydrideand the like, or an organic base such as, for example, a tertiary amine,e.g., N,N-dimethylethanamine, N-(1-methyl-ethyl)-2-propanamine,4-ethylmorpholine and the like may be utilized to pick up the acid whichis liberated during the course of the reaction. In some circumstancesthe addition of a iodide salt, preferably an alkali metal iodide, isappropriate. Somewhat elevated temperatures may enhance the rate of thereaction.

The compounds of formula (I) wherein R² is other than hydrogen, said R²being represented by R^(2-a), and said compounds by formula (I-a), canbe obtained by N-alkylating or N-acylating a 3-piperidinyl-indazole offormula (I-b) wherein R² is hydrogen, with an alkylating or acylatingreagent R^(2-a) -W¹ (IV). ##STR4## In the reagent of formula (IV) W¹represents an appropriate leaving group such as halo, e.g. chloro, bromoand the like; or a sulfonyloxy group, e.g. methanesulfonyloxy,4-methylbenzenesulfonyloxy and the like; in the instances whereinR^(2-a) is C₁₋₆ alkylcarbonyl or optionally substituted phenylcarbonylW¹ may also represent respectively C₁₋₆ alkylcarbonyloxy or optionallysubstituted phenylcarbonyloxy (i.e. R^(2-a) -W¹ is an acid anhydride).Said N-alkylation reaction of (I-b) with a reagent (IV) may be carriedout by stirring and, if desired, heating the reactants, optionally in anappropriate reaction-inert solvent such as, for example, an aromatichydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene, and thelike; a lower alkanol, e.g., methanol, ethanol, 1-butanol and the like;a ketone, e.g., 2-propanone, 4-methyl-2-pentanone and the like; anether, 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; adipolar aprotic solvent, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, nitrobenzene,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone and the like.Further the addition of a base such as, for example, aqueous alkali,e.g. sodium or potassium hydroxide, sodium or potassium carbonate andthe like; or an alkali metal alkoxide such as, for example, sodiummethoxide, sodium ethoxide, potassium tert.-butoxide and the like may beappropriate. In case mixtures of 1- and 2-substituted indazoles areobtained, said mixtures may be separated by the application of art-knownmethods such as, for example, selective crystallization, chromatographyand the like.

The compounds of formula (I) may also be prepared by the cyclizationreaction of an intermediate of formula (V) with an appropriate hydrazinederivative R² --NH--NH₂ (VI) or an acid addition salt thereof. ##STR5##In formula (V) Y represents an appropriate leaving group such as, forexample, halo, e.g. fluoro or chloro; or a nitro group. Said cyclizationreaction may be conducted by stirring, and if desired, heating thereactants in a suitable reaction-inert solvent in the presence of anappropriate base. Suitable solvents generally have a relatively highboiling point and are, for example, water; alkanols, e.g. methanol,ethanol, 1-butanol and the like; diols, e.g. 1,2-ethanediol and thelike; aromatic hydrocarbons, e.g. benzene, methylbenzene,dimethylbenzene and the like; halogenated hydrocarbons, e.g.trichloromethane, tetrachloromethane and the like; ethers, e.g.tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisbutane,1,1'-oxybis-(2-methoxyethane) and the like; dipolar aprotic solvents,e.g. N,N-dimethyl-formamide, N,N-dimethylacetamide, dimethylsulfoxideand the like; or mixtures of such solvents. Appropriate bases preferablyare alkali or earth alkaline metal carbonates or hydrogen carbonatessuch as, for example, sodium hydrogen carbonate, sodium carbonate,potassium carbonate and the like; or amines such asN,N-diethylethanamine, 4-ethylmorpholine,N-(1-methylethyl)-2-propanamine and the like.

Additionally, the compounds of formula (I) may be prepared by thenitrosation of an intermediate aniline of formula ##STR6## with analkali metal nitrite, e.g. sodium nitrite, in an aqueous acidic mediumand treating the thus obtained N-nitroso compound (VIII-a) or, in caseR² is hydrogen, the diazonium salt (VIII-b), ##STR7## wherein A⁻represents the conjugated base of the acid used hereinabove, with anappropriate reducing agent such as, for example, hydrogen in thepresence of a hydrogenation metal catalyst, e.g. Raney nickel or Raneycobalt; or a sulfite, e.g. sodium sulfite, thus yielding thecorresponding hydrazine derivative of formula ##STR8## which in mostinstances spontaneously, or if necessary upon increasing thetemperature, may cyclize to a compound of formula (I).

The compounds of formula (I) may also be prepared following art-knownprocedures n for building up radicals of formula Q. For example, thecompounds of formula (I) wherein Q is radical of formula (b), saidcompounds being represented by formula (I-c), can be obtained from anintermediate of formula (X) by condensation with a reagent of formula(XI), wherein each L independently represents an appropriate leavinggroup. ##STR9## As typical examples of reagents of formula (XI) theremay be mentioned urea, thiourea, carbonic dichloride,1,1'-carbonylbis[1H-imidazole], di(C₁₋₆ alkyl)carbonates such asdimethyl carbonate, diethylcarbonate and the like, chloroformates suchmethyl chloroformate, ethyl chloroformate, phenyl chloroformate and thelike reagents.

The compounds of formula (I-c) can also be prepared by cyclizing anintermediate of formula (XII) with a primary amine of formula (XIII)##STR10## or by cyclizing an isocyanate or isothiocyanate of formula(XIV) with an amine of formula (XIII). ##STR11##

In the foregoing reaction schemes each R¹³ independently represents anappropriate leaving group such as, for example, C₁₋₆ alkyloxy, amino,mono- or di(C₁₋₆ alkyl)amino; and in formula (XII) both R¹³ groups takentogether may also represent -O-. Said cyclization reactions areconveniently conducted by stirring and, if desired, heating thereactants, optionally in a suitable reaction-inert solvent such as analiphatic or aromatic hydrocarbon, e.g. petroleum ether, dimethylbenzeneand the like; a halogenated hydrocarbon, e.g. dichloromethane,trichloromethane, 1,2-dichloroethane and the like; an ether, e.g.tetrahydrofuran, 1,4-dioxane and the like; a ketone, e.g. 2-propanone,4-methyl-2-pentanone and the like.

The compounds of formula (I) wherein Q is a radical of formula (c), saidcompounds being represented by formula (I-d), can be obtained bytreating an intermediate of formula (X) with a carboxylic acid offormula (XV) or, a suitable functional derivative thereof such as anacyl halide, an an anhydride or an ester. In (XV) and in the formulaehereinafter each R¹⁴ independently represents an appropriate leavinggroup such as, for example, hydroxy, halo, C₁₋₆ alkyloxy, C₁₋₆alkylcarbonyloxy, amino, mono- or di-(C₁₋₆ alkyl)amino. ##STR12##

The compounds of formula (I) wherein Q is a radical of formula (a), saidcompounds being represented by the formula (I-e), can be preparedfollowing art-known cyclization procedures for preparingpyrimidin-4-ones such as, for example, by reacting an amine of formula(XVI) with a β-dicarbonyl compound of formula (XVII) or by cyclizing areagent of formula (XVIII) with an enamine of formula (XIX). ##STR13##

Said cyclization reactions may generally be carried out by stirring thereactants, optionally in the presence of a suitable reaction-inertsolvent such as, for example, an aliphatic, alicyclic or aromatichydrocarbon, e.g., hexane, cyclohexane, benzene and the like; orpyridine, N,N-dimethylformamide and the like dipolar aprotic solvents.Elevated temperatures may be appropriate to enhance the reaction rate;more in particular it may be advantageous to carry out the reaction atthe reflux temperature of the reaction mixture.

Following the same procedure the compounds of formula (I-e) can also beprepared by cyclizing an intermediate of formula (XIX) with a reagent offormula (XX). ##STR14##

The compounds of formula (I-e) wherein Z is S, said compounds beingrepresented by the formula (I-e-1), can also be prepared by cyclizing a2-mercaptopyrimidinone of formula (XXI) with a reagent of formula(XXII). ##STR15##

The compounds of formula (I-e-1) wherein A is CR⁸ ═CR⁹, said compoundsbeing represented by the formula (I-e-2), can be prepared by cyclizing a2-mercaptopyrimidinone of formula (XXI) with a reagent of formula(XXIII). ##STR16##

Said cyclization reactions for preparing the compounds of formulae(I-e-1) and (I-e-2) may generally be carried out by stirring thereactants, if desired, in the presence of a suitable reaction-inertsolvent such as, for example, an aliphatic, alicyclic or aromatichydrocarbon, e.g., hexane, cyclohexane, benzene and the like; orpyridine, N,N-dimethylformamide and the like dipolar aprotic solvents.Elevated temperatures may be appropriate to enhance the reaction-rate,more in particular it may be preferred to carry out the reaction at thereflux temperature of the reaction mixture.

The compounds of formula (I) may also be converted into each otherfollowing art-known functional group transformation procedures.

For example, the compounds of formula (I-e) and (I-d) wherein R¹¹ isamino, maybe derived from the corresponding nitro-substitutedquinazolines following art-known nitro-to-amine reduction procedures. Asuitable nitro-to-amine reduction procedure is, for example, catalytichydrogenation in a relatively polar solvent such as, for example, analcohol, e.g. methanol or ethanol, in the presence of an appropriatecatalyst, e.g. platinum-on-charcoal. In some cases it may be useful toadd an appropriate catalyst poison such as thiophene to the reactionmixture.

The compounds of formula (I-e) and (I-d) wherein R¹¹ is phenylmethoxymay be converted into compounds of formula (I-e) and (I-d) wherein R¹¹is hydroxy following art-known catalytic hydrogenolysis procedures; thecompounds of formula (I-e) and (I-d) wherein R¹¹ is amino or hydroxy maybe converted into compounds of formula (I-e) and (I-d) wherein R¹¹ is(C₁₋₁₀ alkylcarbonyl)amino and (C₁₋₁₀ alkyl-carbonyl)oxy respectively byreacting the former compounds with a suitable acylating agent, e.g. anacyl halide or an acid anhydride; the compounds of formula (I-e) and(I-d) wherein R¹¹ is amino may be converted into compounds of formula(I-e) and (I-d) wherein R¹¹ is azido by converting the amino group intoa diazonium group with nitrous acid or an appropriate alkali metal orearth alkaline metal salt thereof and subsequently converting saiddiazonium group into an azido group with sodium azide or any othersuitable alkali metal or earth alkaline metal azide.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, such as hydrohalic acid, e.g. hydrochloric,hydrobromic acid and the like, sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butanedioic,(E)-2-butanedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methyl-benzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted into the free base form bytreatment with alkali. The term acid addition salt as used hereinabovealso comprises the solvates which the compounds of formula (I) are ableto form and said solvates are meant to be included within the scope ofthe present invention. Examples of such solvates are e.g., the hydrates,alcoholates and the like.

A number of intermediates and starting materials in the foregoingpreparations are known compounds which may be prepared according toart-known methodologies of preparing said or similar compounds. Theintermediates of formula (II) and their preparations are described inU.S. Pat. Nos. 4,335,127, 4,342,870, 4,443,451 and 4,485,107, and in thereferences cited therein. The intermediates of formula (III) are knownfrom EP-A-0,135,781.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereochemically isomeric forms thereof, are potentantagonists of neurotransmitters and in particular of the mediatorsserotonin and dopamine. Antagonizing said mediators will suppress orrelieve a variety of symptoms associated with phenomena induced by therelease, in particular the excessive release, of these mediators.Therapeutic indications for using the present compounds are mainly inthe CNS area, the gastrointestinal and cardiovascular field and relateddomains. Serotonin antagonists are reportedly effective in combattingpsychoses, aggressive behaviour, anxiety, depression and migraine.Combined serotonin-dopamine antagonists are especially interesting asthey appear to offer relief of both the positive and negative symptomsof schizophrenia. Therapeutic applications in the gastrointestinal fieldcomprise their use as, for instance, antidiarrhoeals, inhibitors ofgastro-oesophageal reflux and particularly antiemetics, e.g. in cancerpatients receiving chemotherapy and radiation treatment. Further,serotonin is a potent broncho- and vasoconstrictor and thus the presentantagonists may be used against hypertension and vascular disorders. Inaddition, serotonin antagonists have been associated with a number ofother properties such as, the suppression of appetite and promotion ofweight loss, which may prove effective in combatting obesity; and alsothe alleviation of withdrawal symptoms in addicts trying to discontinuedrinking and smoking habits.

The compounds of the instant invention are particularly useful asantihypertensive agents because of their ability to depresssignificantly both systolic and diastolic blood pressure in warm-bloodedanimals. The antihypertensive effect of the instant compounds isevidenced in the "Blood pressure lowering effect in spontaneoushypertensive rats" test. Particularly interesting are also theobservations made in the combined "Apomorphine, tryptamine andnorepinephrine in rats" test: contrary to most structurally related3-piperidinyl benzazoles, the instant compounds do not show significantactivity on the central nervous system, but rather act peripherally.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of the particular compound, in acidaddition salt or base form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, which maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, foradministration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wettable agent, optionally combined withsuitable additives of any nature in minor proportions, which additivesdo not cause any significant deleterious effects on the skin. Saidadditives may facilitate the administration to the skin and/or may behelpful for preparing the desired compositions. These compositions maybe administered in various way, e.g., as a transdermal patch, as aspot-on or as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable o solutions or suspensions, teaspoonfuls, tablespoon fuls andthe like, and segregated multiples thereof.

In view of the usefulness of the subject compounds in the treatment ofhypertension it is evident that the present invention provides a methodof treating warm-blooded animals suffering from hypertension, saidmethod comprising the systemic administration of a pharmaceuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof in admixture with a pharmaceuticalcarrier. Those of skill in the treatment of hypertension could easilydetermine the effective amount from the test results presented here. Ingeneral it is contemplated that an effective amount would be from 0.01mg/kg to 4 mg/kg body weight, more preferably from 0.04 mg/kg to 2 mg/kgbody weight per day.

It is evident that said effective amount may be lowered or increaseddepending on the response of the treated subject and/or depending on theevaluation of the physician prescribing the compounds of the instantinvention. The effective amount ranges mentioned hereinabove aretherefore guidelines only and are not intended to limit the scope or useof the invention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated all partstherein are by weight.

EXPERIMENTAL PART A. Preparation of Intermediates EXAMPLE 1

a) To a stirred mixture of 15.8 parts of a sodium hydride dispersion 50%and 660 parts of dimethyl sulfoxide were added portionwise 78.4 parts of1-acetyl-4-(6-fluoro-2H-indazol-3-yl)piperidine under nitrogenatmosphere. Upon complete addition, stirring was continued for 1 hour atroom temperature. 42 Parts of chloromethylbenzene were added dropwiseduring 45 minutes. Upon completion, stirring was continued overnight atroom temperature. The reaction mixture was poured into crushed ice andthe product was extracted with dichloromethane. The extract was dried,filtered and evaporated. The residue was purified by columnchromatography (HPLC) over silica gel using a mixture of methylbenzeneand methanol (90:10 by volume) as eluent. The first fraction wascollected and the eluent was evaporated, yielding 91 parts (86.3%) of1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl]piperidine as aresidue (int. 1).

b) A mixture of 8 parts of1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl]-piperidine and 70parts of a hydrochloric acid solution 6N was stirred for 6 hours atreflux temperature. The reaction mixture was evaporated and the oilyresidue was crystallized from 2-propanol. The product was filtered offand dried, yielding 2 parts (25.1%) of6-fluoro-2-(phenylmethyl)-3-(4-piperidinyl)-2H-indazolemonohydrochloride; mp. >300° C. (int. 2).

EXAMPLE 2

a) A mixture of 50 parts of 5-methyl-3-isoxazolamine, 70 parts of3-acetyl-4,5-dihydro-2(3H)-furanone, 435 parts of methylbenzene and 16parts of polyphosphoric acid was stirred and refluxed for 3 hours usinga water separator. The reaction mixture was concentrated in vacuo,yielding 99 parts (95.1%) of4,5-dihydro-3-[1-(5-methyl-3-isoxazolyl)imino]ethyl]-2(3H)-furanone asan oily residue (int. 3).

b) To a stirred mixture of 98 parts of4,5-dihydro-3-[1-(5-methyl-3-isoxazolyl)imino]-ethyl]-2-(3H)-furanone,348 parts of methylbenzene and 300 parts of trichloromethane were addeddropwise 150 parts of phosphoryl chloride. Upon complete addition,stirring was continued for 3 hours at reflux temperature. The reactionmixture was concentrated to half its volume and the residue was pouredinto crushed ice. The whole was treated with an ammonium hydroxidesolution and the product was extracted twice with 240 parts of4-methyl-2-pentanone. The combined extracts were dried, filtered andevaporated in vacuo. The residue was dissolved in trichloromethane,filtered over silica gel and the filtrate was concentrated in vacuo. Theresidue was crystallized form a mixture of methylbenzene and2,2'-oxybispropane, yielding 96 parts (88.2%) of6-(2-chloroethyl)-2,5-dimethyl-7H-isoxazolo[2,3-a]pyrimidin-7-one; mp.165° C. (int. 4).

B. Preparation of Final Compounds EXAMPLE 3

A mixture of 4 parts of 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione,4,4 parts of 6-fluoro-1-methyl-3-(1-piperidinyl)-1H-indazolemonohydrochloride, 10 parts of sodium carbonate, 0.1 parts of potassiumiodide and 144 parts of 4-methyl-2-pentanone was stirred overnight atreflux temperature. After cooling, the reaction mixture was poured intowater. The separated organic layer was dried, filtered and evaporated.The residue was purified by column chromatography over silica gel usinga mixture of trichloromethane and methanol (95:5 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was crystallized from acetonitrile. The product was filtered offand dried, yielding 4 parts (59.3%) of3-[2-[4-(6-fluoro-1-methyl-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)quinazolinedione;mp. 250.1° C. (compound 1).

EXAMPLE 4

A mixture of 4.4 parts of6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrobromide, 3.7 parts of 6-fluoro-3-(4-piperidinyl)-1H-indazoledihydrochloride, 4.25 parts of sodium carbonate and 120 parts of4-methyl-2-pentanone was stirred for 6 hours at reflux temperature.After cooling, the reaction mixture was filtered, The precipitate wasstirred in water and the whole was filtered again. The precipitatedproduct was purified by column chromatography over silica gel using amixture of trichloromethane and methanol (90:10 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was crystallized from 2-propanol. The product was filtered offand dried, yielding 2.5 parts (48.3%) of6-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 207.6° C. (compound 2).

EXAMPLE 5

0.7 Parts of a sodium hydride dispersion 50% in mineral oil weresuspended in petroleum ether under a nitrogen atmosphere. The solventwas decanted and 55 parts of dimethyl sulfoxide were added. 6 Parts of6-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onewere added portionwise while stirring at room temperature. Upon completeaddition, stirring was continued for 1 hour at room temperature. Afterthe dropwise addition of 2.6 parts of 1-chloromethyl-4-methoxybenzene,the reaction mixture was stirred overnight at room temperature. Thewhole was poured into water and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CHCl₃ /CH₃ OH95:5). The eluent of the desired fraction was evaporated and the residuewas crystallized from 2-propanol. The product was filtered off anddried, yielding 2.4 parts (30.0%) of 6-[2-[4-[6-fluoro-1-[(4-methoxyphenyl)methyl]-1H-indazol-3-yl]-1-piperidinyl]ethyl]-2,3-dihydro-7methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 145.8° C. (compound 30).

EXAMPLE 6

A mixture of 3.2 parts of3-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one,27 parts of acetic anhydride and 15.7 parts of acetic acid was stirredfor 2 hours at reflux temperature. The reaction mixture was evaporatedand the residue was poured into 100 parts of water. After basifying withNH₄ OH, the product was extracted with dichloromethane. The extract wasdried, filtered and evaporated and the residue was crystallized from2-propanol, yielding 3.3 parts (95.3%) of3-[2-[4-(1-acetyl-6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one;mp. 210.3° C. (compound 46). All other compounds listed in tables 1 to 3were obtained following methods of preparation analogous to thosedescribed in examples 2 to 6, as is indicated in the column headed byEx. No.

                  TABLE 1                                                         ______________________________________                                         ##STR17##                                                                    Comp. Ex.                                                                     No.   No.    R.sup.2    R.sup.3                                                                             Physical Data                                   ______________________________________                                        3     3      4-FC.sub.6 H.sub.4                                                                       F     HCl/mp. 291.5° C.                        4     3      H          F     mp. 278.9° C.                            5     3      CH.sub.2 C.sub.6 H.sub.5                                                                 F     mp. 223.5° C.                            53    3      H          OCH.sub.3                                                                           2 HCl/H.sub.2 O/mp. 244.3° C.            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR18##                                                                    Comp.   Ex.                                                                   No.     No.        R.sup.2      Physical Data                                 ______________________________________                                        6       4          H            mp. 259.7° C.                          7       3          CH.sub.3     mp. 143.8° C.                          8       3          CH.sub.2 C.sub.6 H.sub.5                                                                   mp. 98.3° C.                           ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________     ##STR19##                                                                    Comp.                                                                             Ex.                                                                       No. No.                                                                              ZA             R.sup.2   R.sup.3                                                                           Physical Data                             __________________________________________________________________________     9  3  CHCHCHCH       4-FC.sub.6 H.sub.4                                                                      F   mp. 147.5° C.                      10  3  CHCHCHCH       H         F   mp. 259.5° C.                      11  3  CHCHCHCH       CH.sub.3  F   mp. 149.8° C.                      12  3  CHCHCHCH       CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 131.4° C.                      13  3   (CH.sub.2).sub.4                                                                            H         F   mp. 236.2° C.                      14  3  (CH.sub.2).sub.4                                                                             CH.sub.3  F   mp. 168.1° C.                      15  3  (CH.sub.2).sub.4                                                                             CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 162.1° C.                      16  3  SCHCH          4-FC.sub.6 H.sub.4                                                                      F   (E)-2-butenedioate/                                                           mp. 232.4° C.                      17  3  SCHCH          H         F   1/2 H.sub.2 O/mp. 190.1° C.        18  3  SCHCH          CH.sub.3  F   mp. 139.9° C.                      19  3  SCHCH          CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 127.6° C.                      20  4  SCHC(CH.sub.3) 4-FC.sub.6 H.sub.4                                                                      F   1/2 (E)-2-butenedioate/                                                       H.sub.2 O/mp. 165.0° C.            21  3  SCHC(CH.sub.3) CH.sub.3  F   mp. 170.0° C.                      22  4  SCHC(CH.sub.3) H         F   mp. 232.4° C.                      23  3  SCHC(CH.sub.3) CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 141.1° C.                      24  3  SCHC(CH.sub.3) 2-CH.sub.2 C.sub.6 H.sub.5                                                              F   mp. 180.0° C.                      25  3  S(CH.sub.2).sub.2                                                                            CH.sub.3  F   mp. 157.6° C.                      26  3  S(CH.sub.2).sub.2                                                                            CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 150.2° C.                      27  3  S(CH.sub.2).sub.2                                                                            2-CH.sub.2 C.sub.6 H.sub.5                                                              F   mp. 175.2° C.                      28  3  C(CH.sub.3)CHCHCH                                                                            H         F   mp. 213.1° C.                      29  3  C(CH.sub.3)CHCHCH                                                                            CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 139° C.                        30  5  S(CH.sub.2).sub.2                                                                            CH.sub.2 -(4-OCH.sub.3 C.sub.6 H.sub.4)                                                 F   mp. 145.8° C.                      31  3  CHC(CH.sub.3)O CH.sub.2 C.sub.6 H.sub.5                                                                F   mp. 136.1° C.                      32  4  SCHC(CH.sub.3) CH.sub.2 -(4-FC.sub.6 H.sub.4)                                                          F   mp. 139.2° C.                      33  3  C(CH.sub.3)CHCHCH                                                                            H         OCH.sub.3                                                                         mp. 210.0° C.                      34  3  SCHCH          H         OCH.sub.3                                                                         mp. 183.2° C.                      35  3  SCHCH          H         H   2 HCl/mp. 196.4° C.                36  5  (CH.sub.2).sub.4                                                                              ##STR20##                                                                              F   (E)-2-butenedioate(1:1) mp.                                                   151.2° C.                          37  3  C(CH.sub.3)CHCHCH                                                                            CH.sub.2 CH.sub.2 OH                                                                    F   mp. 176.0° C.                      38  3  (CH.sub.2).sub.4                                                                             CH.sub.2 CH.sub.2 OH                                                                    F   mp. 140.1° C.                      39  3  S(CH.sub.2).sub.2                                                                            CH.sub.2 CH.sub.2 OH                                                                    F   mp. 165.6° C.                      40  3  C(CH.sub.3)CHCHCH                                                                            H         H   mp. 180.2° C.                      41  3  CHC(CH.sub.3)O CH.sub.3  F   mp. 157.7° C.                      42  3  (CH.sub.2).sub.4                                                                             H         H   mp. 188.1° C.                      43  3  SCHCH          CH.sub.2 CH.sub.2 OH                                                                    F   mp. 197.2° C.                      44  5  (CH.sub.2).sub.4                                                                              ##STR21##                                                                              F   mp. 179.4° C.                      45  3  SCH.sub.2 CH.sub.2                                                                           H         H   mp. 210.3° C.                      46  6  C(CH.sub.3)CHCHCH                                                                            COCH.sub.3                                                                              F                                             47  6  C(CH.sub.3)CHCHCH                                                                            CO(4-ClC.sub.6 H.sub.5)                                                                 F   mp. 181.6° C.                      48  6  C(CH.sub.3)CHCHCH                                                                            COOC.sub.2 H.sub.5                                                                      F   mp. 183.1° C.                      49  3  SCH.sub.2 CH.sub.2                                                                           H         H                                             50  6  C(CH.sub.3)CHCHCH                                                                            COCH.sub.3                                                                              H   mp. 160.7° C.                      51  6  (CH.sub.2).sub.4                                                                             COCH.sub.3                                                                              H   mp. 149.3° C.                      52  3  SCH.sub.2 CH.sub.2                                                                           COCH.sub.3                                                                              H                                             __________________________________________________________________________

C) Pharmacological Examples

The activity of the subject compounds as antagonists ofneurotransmitters is evidenced by the experimental data obtained in atleast one of two different test procedures, viz., the combinedapomorphine-, tryptamine- and norepinephrine tests in rats and theapomorphine test in dogs. The tests are carried out following theprocedures described hereafter and the experimental data are summarizedin table 4. The antihypertensive effect of the instant compounds isevidenced by the "Blood pressure lowering effect in spontaneoushypertensive rats" test. The experimental data are summarized in table5.

EXAMPLE 7 The Combined Apomorphine (APO)-, Tryptamine (TRY)- andNorepinephrine (NOR) Test in Rats

The experimental animals used in this test were adult male Wistar rats(weight 240±10 g). After an overnight fast, the animals were treatedsubcutaneously or orally with an aqueous solution of the compound underinvestigation (1 ml/100 g body weight) (time=zero) and put in isolatedobservation cages. Thirty minutes thereafter (time=30 minutes) 1.25mg/kg of apomorphine hydrochloride (APO) was injected intravenously andthe rats were observed over a 1 hour period for the presence or absenceof the following apomorphine-induced phenomena: agitation andstereotypic chewing. At the end of this 1 hour period (time=90 minutes)the same animals were injected intravenously with 40 mg/kg of tryptamine(TRY) and the presence of the typical tryptamine-induced bilateral tonicseizures and hyperaemia of the ears was noted. Two hours afterpretreatment (time=120 minutes) finally, the same animals werechallenged with 1.25 mg/kg intravenously of norephinephrine (NOR) andpossible mortality was looked for up to 60 minutes later.

The table 4 gives the ED₅₀ -values of a number of the compounds underconsideration. As used herein, the ED₅₀ -value represents the dose whichprotects 50% of the animals from apomorphine-, tryptamine- ornorepinephrine-induced phenomena.

The Apomorphine Test in Dogs (APO-Dog)

The method used is described by P. A. J. Janssen and C. J. E. Niemegeersin Arzneim.-Forsch. (Drug Res.), 9, 765-767 (1959). The compounds listedin table 4 were administered subcutaneously or orally to beagle dogs atdifferent doses and the animals were challenged one hour thereafter witha standard dose of 0.31 mg/kg (s.c.) of apomorphine.

The table 4 gives the ED₅₀ -values of a number of the compounds underconsideration. As used herein, the ED₅₀ value represents the dose whichprotects 50% of the animals from emesis.

The compounds listed in table 4 are not given for the purpose oflimiting the invention thereto but only to exemplify the usefulpharmacological activities of all the compounds within the scope offormula (I).

                  TABLE 4                                                         ______________________________________                                        Combined test in rats; ED.sub.50 in mg/kg                                                    (TRY)-   (TRY)-                                                Comp.          convul-  hyper-       (APO)-dog test,                          No.   (APO)    sions    aemia (NOR)  ED.sub.50 in mg/kg                       ______________________________________                                         2    5        5        0.005 0.31   0.002                                     9    >10      5        0.08  5                                               11    5        0.31     0.005 0.08   0.12                                     13    >10      1.25     0.02  0.31   0.015                                    16    >10      5        0.08  >10                                             17    5        5        0.03  2.0    0.004                                    18    5        1.25     0.005 1.25   0.2                                      20    >10      ≧10                                                                             0.08  >10                                             21    1.25     0.08     0.005 0.31   0.12                                     25    >10      1.25     0.01  0.31   <0.015                                   29    1.25     5        ≦0.16                                                                        1.25   0.004                                    30    >10      10       0.08  5      >0.63                                    31    >10      1.25     0.02  0.31   >0.63                                    34    >10      >10      1.25  1.25   >0.01                                    ______________________________________                                    

EXAMPLE 8 Blood pressure lowering effect in spontaneous hypertensiverats (SHR)

Adult spontaneous hypertensive rats (6 months of age) were anesthetizedby ether inhalation. The femoral artery was dissected and cannulated,and the catheter was connected to a strain-gauge blood pressuretransducer. When the animals were fully awake, they were restrained andthe systolic and diastolic arterial blood pressure were continuouslyrecorded. An observation period of at least 30 min. preceded theadministration of the test compound. All test compounds were dissolvedin 20% polypropylene glycol and injected intraperitoneally. Afteradministration of the test drug the systolic and diastolic arterialblood pressure and the heart rate were recorded during a period of 120minutes. The average blood pressure and heart rate was calculated fromthe results obtained at various time intervals after administration ofthe test drug. The following table illustrates the lowering of thesystolic and diastolic blood pressure.

    ______________________________________                                        Comp.                                                                         No.         SBP (mm Hg) DBP (mm Hg)                                           ______________________________________                                         2          -140        -100                                                   9          -40         -30                                                   11          -130        -90                                                   13          -120        -80                                                   18          -90         -70                                                   25          -170        -90                                                   28          -140        -100                                                  29          -30         -30                                                   30          -70         -55                                                   31          -80         -60                                                   34          -20         -10                                                   46          -100        -65                                                   47          -90         -60                                                   48          -110        -85                                                   53          -60         -45                                                   ______________________________________                                    

D) Composition Examples EXAMPLE 9: ORAL DROPS

500 Parts of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60°-80° C. After 30°-40° C.there were added 35 l of polyethylene glycol and the mixture was stirredwell. Then there was added a solution of 1750 parts of sodium saccharinin 2.5 l of purified water and while stirring there were added 2.5 l ofcocoa flavor and polyethylene glycol q.s. to a volume of 50 l, providingan oral drop solution comprising 10 mg/ml of A.I. The resulting solutionwas filled into suitable containers.

EXAMPLE 10: ORAL SOLUTION

9 Parts of methyl 4-hydroxybenzoate and 1 part of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 parts of2,3-dihydroxybutanedioic acid and thereafter 20 parts of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Parts of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE 11: CAPSULES

20 Parts of the A.I., 6 parts sodium lauryl sulfate, 56 parts starch, 56parts lactose, 0.8 parts colloidal silicon dioxide, and 1.2 partsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

EXAMPLE 12: FILM-COATED TABLETS Preparation of Tablet Core

A mixture of 100 parts of the A.I., 570 parts lactose and 200 partsstarch was mixed well and thereafter humidified with a solution of 5parts sodium dodecyl sulfate and 10 parts polyvinylpyrrolidone(Kollidon-K 90®) in about 200 ml of water. The wet powder mixture wassieved, dried and sieved again. Then there was added 100 partsmicrocrystalline cellulose (Avicel®) and 15 parts hydrogenated vegetableoil (Sterotex®). The whole was mixed well and compressed into tablets,giving 10,000 tablets, each containing 10 mg of the active ingredient.

Coating

To a solution of 10 parts methyl cellulose (Methocel 60 HG ®) in 75 mlof denaturated ethanol there was added a solution of 5 parts of ethylcellulose (Ethocel 22 cps®) in 150 ml of dichloromethane. Then therewere added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10Parts of polyethylene glycol was molten and dissolved in 75 ml ofdichloromethane. The latter solution was added to the former and thenthere were added 2.5 parts of magnesium octadecanoate, 5 parts ofpolyvinylpyrrolidone and 30 ml of concentrated colour suspension(Opaspray K-1-2109®) and the whole was homogenated. The tablet coreswere coated with the thus obtained mixture in a coating apparatus.

EXAMPLE 13: INJECTABLE SOLUTION

1.8 Parts methyl 4-hydroxybenzoate and 0.2 parts propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 parts lactic acid, 0.05 parts propylene glycol and 4 parts of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration (U.S.P. XVII p. 811) andfilled in sterile containers.

EXAMPLE 14: SUPPOSITORIES

3 Parts A.I. was dissolved in a solution of 3 parts2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Partssurfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 partswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37°-38° C. to form 100 suppositories each containing 30mg/ml of the A.I..

We claim:
 1. A chemical compound having the formula ##STR22## apharmaceutically acceptable acid addition salt or a stereochemicallyisomeric form thereof, whereinR¹ is hydrogen or C₁₋₆ alkyl; R² ishydrogen; C₁₋₆ alkyl; hydroxyC₁₋₆ alkyl; phenyl optionally substitutedwith up to three substituents independently selected from C₁₋₆ alkyl,C₁₋₆ alkyloxy, hydroxy, halo, amino, nitro and trifluoromethyl; arylC₁₋₆alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl or phenylcarbonyl,wherein phenyl is optionally substituted with up to three substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy, halo,amino, nitro and trifluoromethyl; R³ and R⁴ each independently arehydrogen, halo, hydroxy, C₁₋₆ alkyloxy or C₁₋₆ alkyl; Alk is C₁₋₄alkanediyl; and Q is a bicyclic heterocyclic radical of formula##STR23## wherein R⁵ is hydrogen or C₁₋₆ alkyl; Z is --S-- or --CR⁶ =CR⁷--; said R⁶ and R⁷ each independently being hydrogen or C₁₋₆ alkyl; or Zis --CH₂ -- wherein one hydrogen atom may be replaced by hydroxy or C₁₋₆alkyl; A is a bivalent radical --CH₂ --CH₂ -- or --CH₂ --CH₂ --CH₂ --wherein in the latter two radicals one or two hydrogen atoms may bereplaced by C₁₋₆ alkyl; or A is a bivalent radical --CR⁸ ═CR⁹, whereinR⁸ and R⁹ each independently are hydrogen, halo, amino or C₁₋₆ alkyl; orwhen Z is --S--, then A may also be --CR¹⁰ ═N--, R¹⁰ being hydrogen orC₁₋₆ alkyl; or when Z is --CR⁶ ═CR⁷ --, then A also may be --O--; and Y¹and Y² each independently are O and S; R¹¹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆ alkyloxy, trifluoromethyl, nitro, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₁₀ aklylcarbonylamino, cyano, hydroxy, C₁₋₁₀alkylcarbonyloxy, phenylmethoxy or azido; R¹² is hydrogen or halo; andaryl is phenyl optionally substituted with up to three substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy, halo,amino, nitro and trifluoromethyl; pyridinyl, furanyl or C₁₋₆ alkylsubstituted furanyl.
 2. A chemical compound according to claim 1 whereinR¹ is hydrogen; R² is substituted on N¹, R³ and R⁴ each independentlyare hydrogen, C₁₋₆ alkyloxy or halo; Q is a radical of formula (a)wherein R⁵ is C₁₋₆ alkyl.
 3. A chemical compound according to claim 1wherein R² is hydrogen, C₁₋₆ alkyl, phenyl optionally substituted withhalo or trifluoromethyl, or phenylmethyl optionally substituted withhalo, C₁₋₆ alkyloxy or trifluoromethyl; R³ is halo; R⁴ is hydrogen.
 4. Achemical compound according to claim 1 wherein R³ is 6-fluoro.
 5. Anantihypertensive composition comprising one or more inert carriers andas active ingredient an antihypertensively effective amount of achemical compound as claimed in any of claims 1 to
 4. 6. The compound ofclaim 1 wherein said compound is selected from the group consistingof:6-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-[2-[4-(6-fluoro-1-methyl-1H-indazol-3-yl)-1-piperidinyl]-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;3-[2-[4-(6fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one;6-[2-[4-(6-fluoro-1-methyl-1H-idazol-3-yl)-1-piperidinyl]-ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-[2-[4-(6-fluor-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one;3-[2-[4-(1-acetyl-6-fluoro-1H-indazol-3-yl)-1-piperidinyl]-ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one;and ethyl3-[1-[2-(2,9-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl]-4-piperidinyl]-6-fluoro-1H-indazole-1-carboxylate.4